INTRODUCTION: Osteoarthritis (OA) is one of the major menaces to human health. Currently, no sufficiently effective medications are available to treat OA clinically. OA is an inflammatory joint disorder. The overproduction of reactive oxygen species (ROS) plays a critical role in initiating and developing OA pathogenesis. ROS scavenging has become a vital target for OA therapy. Although chromium sesquioxide (CrO) nanoparticle has been proven to have excellent ROS scavenging ability, its clinical application is limited due to its poor biocompatibility. Polydopamine (PDA) is an excellent carrier with outstanding biocompatibility. PDA-based nanomaterials exhibit significant potential for various ROS-related diseases. METHODS: PDA was synthesized through oxidative autopolymerization of dopamine in an alkaline environment. Subsequently, the novel nanozyme PDA-CrO was synthesized by loading CrO onto PDA nanoparticles with the assistance of hydrazine hydrate. Afterward, the cytotoxicity and ROS scavenging capacity of PDA-CrO were examined. Finally, the ability of PDA-CrO to treat OA was explored at both cellular and animal levels. RESULTS: PDA-CrO had low cytotoxicity and toxic side effects in vivo. Moreover, PDA-CrO₃ exhibited a remarkable capacity to scavenge ROS both in cell-free in vitro systems, such as kit-based assays, and in cellular models. It also dramatically decreased the transcriptional level of inflammation-associated genes and the secretion of inflammatory factors of the OA chondrocytes. In animal experiments, PDA-CrO markedly suppressed the progression of OA. CONCLUSION: PDA-CrO nanozyme had good biocompatibility and could effectively suppress the development of OA by efficiently scavenging ROS, which has important application prospects in OA treatment. This study might offer some new ideas for the treatment of ROS-related diseases.